Enalapril

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Oral, as maleate:

Epaned: 1 mg/mL (150 mL) [contains sodium benzoate]

Solution Reconstituted, Oral, as maleate:

Epaned: 1 mg/mL (150 mL [DSC]) [contains methylparaben, propylparaben, saccharin sodium; berry-citrus flavor]

Tablet, Oral, as maleate:

Vasotec: 2.5 mg, 5 mg, 10 mg, 20 mg [scored]

Generic: 2.5 mg, 5 mg, 10 mg, 20 mg

Pharmacology

Mechanism of Action

Competitive inhibitor of angiotensin-converting enzyme (ACE); prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor; results in lower levels of angiotensin II which causes an increase in plasma renin activity and a reduction in aldosterone secretion

Pharmacokinetics/Pharmacodynamics

Absorption

55% to 75%

Metabolism

Prodrug, undergoes hepatic biotransformation to enalaprilat

Excretion

Urine (61%; 18% of which was enalapril, 43% was enalaprilat); feces (33%; 6% of which was enalapril, 27% was enalaprilat) (Ulm 1982)

Onset of Action

~1 hour; Peak effect: 4 to 6 hours

Time to Peak

Serum: Oral: Enalapril: 0.5 to 1.5 hours; Enalaprilat (active metabolite): 3 to 4.5 hours

Duration of Action

12 to 24 hours

Half-Life Elimination

Enalapril: CHF: Neonates (n=3, PNA: 10 to 19 days): 10.3 hours (range: 4.2 to 13.4 hours) (Nakamura 1994); CHF: Infants and Children ≤6.5 years of age (n=11): 2.7 hours (range: 1.3 to 6.3 hours) (Nakamura 1994); Adults: Healthy: 2 hours; CHF: 3.4 to 5.8 hours

Enalaprilat: CHF: Neonates (n=3, PNA: 10 to 19 days): 11.9 hours (range: 5.9 to 15.6 hours) (Nakamura 1994); CHF: Infants and Children ≤6.5 years of age (n=11): 11.1 hours (range: 5.1 to 20.8 hours) (Nakamura 1994); Infants 6 weeks to 8 months of age: 6 to 10 hours (Lloyd 1989); Adults: ~35 hours (Till 1984; Ulm 1982)

Protein Binding

~50% (Davies 1984)

Use in Specific Populations

Special Populations: Renal Function Impairment

In those with glomerular filtration rate (GFR) 30 mL/minute or less, the peak and trough enalaprilat levels increase, T_max increases, and time to steady state may be delayed.

Use: Labeled Indications

Heart failure: Treatment of symptomatic heart failure with reduced ejection fraction (HFrEF) to improve symptoms, increase survival, and decrease hospitalizations. In patients with stable asymptomatic HFrEF, enalapril decreases the risk of developing overt heart failure and the incidence of heart failure hospitalizations.

Hypertension: Management of hypertension, alone or in combination with other antihypertensive agents

Use: Off Label

Non-ST-elevation acute coronary syndromeyes

Based on the 2014 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the management of patients with non-ST-elevation acute coronary syndromes (NSTE-ACS), an angiotensin-converting enzyme (ACE) inhibitor should be initiated and continued indefinitely after NSTE-ACS in patients with a left ventricular ejection fraction (LVEF) ≤40% and in those with hypertension, diabetes mellitus, or stable chronic kidney disease (CKD) unless contraindicated. Use of an ACE inhibitor may also be useful in all other patients with cardiac or other vascular disease.

Posttransplant erythrocytosis (renal transplant recipients)c

Data from a limited number of small clinical trials suggest that enalapril may be beneficial for the treatment of renal transplant recipients who have posttransplant erythrocytosis Ok 1995, Perazella 1995, Rell 1994, Yildiz 2001.

Proteinuric chronic kidney disease (diabetic or nondiabetic)yes

Based on the 2013 Kidney Disease Improving Global Outcomes (KDIGO) guidelines, the use of an ACE inhibitor or an angiotensin receptor blocker (ARB) is recommended in patients with proteinuric CKD to prevent progression of CKD.

Stable coronary artery diseaseyes

Based on the 2012 ACC/AHA guideline for the diagnosis and management of patients with stable ischemic heart disease, an ACE inhibitor or ARB should be prescribed in all patients with stable ischemic heart disease who also have hypertension, diabetes mellitus, LVEF <40%, or CKD unless contraindicated.

ST-elevation myocardial infarctionyes

Based on the 2013 ACC/AHA guidelines for the management of patients with ST-elevation acute coronary syndromes (STE-ACS), an ACE inhibitor should be initiated within the first 24 hours to all patients with STE-ACS with anterior location, heart failure, or LVEF ≤40%, unless contraindicated. It is also reasonable to initiate an ACE inhibitor in all patients with STE-ACS.

Contraindications

Hypersensitivity to enalapril or any component of the formulation; angioedema related to previous treatment with an ACE inhibitor; idiopathic or hereditary angioedema; concomitant use with aliskiren in patients with diabetes mellitus; coadministration with or within 36 hours of switching to or from a neprilysin inhibitor (eg, sacubitril).

Documentation of allergenic cross-reactivity for ACE inhibitors is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Canadian labeling: Additional contraindications (not in US labeling): Concomitant use with aliskiren-containing drugs in patients with moderate-to-severe renal impairment (GFR <60 mL/minute/1.73 m²)

Dosage and Administration

Dosing: Adult

Acute coronary syndrome:

Non-ST elevation acute coronary syndrome (off-label use): Note: Patients should be hemodynamically stable before initiation. Use as a component of an appropriate medical regimen, which may also include antiplatelet agent(s), a beta-blocker, and a statin. Continue angiotensin-converting enzyme inhibitor therapy indefinitely for patients with concurrent diabetes, left ventricular ejection fraction ≤40%, hypertension, or stable chronic kidney disease (AHA/ACC [Amsterdam 2014]). Dosing is based on expert opinion and general dosing range in manufacturer's labeling.

Oral: Initial: 2.5 to 5 mg in 1 or 2 divided doses (depending on initial blood pressure); titrate slowly based on tolerability and response up to 40 mg/day in 1 or 2 divided doses (Reeder 2018a; Reeder 2018b).

ST-elevation myocardial infarction (off-label use): Note: Patients should be hemodynamically stable before initiation. Use as a component of an appropriate medical regimen, which may also include antiplatelet agent(s), a beta-blocker, and a statin (ACCF/AHA [O'Gara 2013]). Dosing is based on expert opinion and general dosing range in manufacturer's labeling.

Oral: Initial: 2.5 to 5 mg in 1 or 2 divided doses (depending on initial blood pressure); titrate slowly based on tolerability and response up to 40 mg/day in 1 or 2 divided doses (Reeder 2018a; Reeder 2018b).

Heart failure with reduced ejection fraction: Oral: Initial: 2.5 mg twice daily; as tolerated, may increase every 1 to 2 weeks to a target dose of 10 to 20 mg twice daily (ACCF/AHA [Yancy 2017]; Gottlieb 2019). In hospitalized patients, the dose may be titrated at 1- to 2-day intervals (Gottlieb 2019).

Hypertension: Note: For initial treatment in patients with blood pressure ≥20/10 mm Hg above goal, may be used in combination with another appropriate agent (eg, long-acting dihydropyridine calcium channel blocker, thiazide diuretic). For patients <20/10 mm Hg above goal, some experts recommend an initial trial of monotherapy; however, over time, many patients will require combination therapy (ACC/AHA [Whelton 2018]; Mann 2019a).

Oral: Initial: 5 mg in 1 or 2 divided doses; evaluate response every 4 to 6 weeks and titrate dose in 1-step increments (eg, increase the daily dose by doubling) as needed, up to 40 mg/day in 1 or 2 divided doses (ACC/AHA [Whelton 2018]; Mann 2019a).

Posttransplant erythrocytosis (renal transplant recipients) (off-label use): Note: For patients with a hemoglobin concentration >17 g/dL (Brennan 2019).

Oral: Initial: 2.5 or 5 mg daily; if inadequate response seen within 4 weeks, may titrate up to 40 mg/day based on hemoglobin and blood pressure response; if hemoglobin remains >17 g/dL after an additional 4 weeks, consider additional therapy (eg, phlebotomy) (Brennan 2019; MacGregor 1996; Ok 1995; Perazella 1995; Rell 1994; Yildiz 2001).

Proteinuric chronic kidney disease (diabetic or nondiabetic) (off-label use): Dosing recommendations based on expert opinion and general dosing range in manufacturer's labeling:

Oral: Initial: 2.5 to 5 mg in 1 or 2 divided doses depending on blood pressure; titrate slowly based on tolerability and response up to 40 mg/day in 1 or 2 divided doses. Target to an appropriate blood pressure goal and a proteinuria goal of <1 g/day (KDIGO 2013; Mann 2019b; Praga 2003).

IgA nephropathy: In addition to an appropriate blood pressure goal, a proteinuria goal of <1 g/day is also generally recommended (KDIGO 2012). Some experts treat to a proteinuria goal of <500 mg/day. If proteinuria goal is not met with monotherapy at the maximum dose, consider adding other modalities and/or agents (Cattran 2019).

Conversion from IV enalaprilat to oral enalapril therapy: If not concurrently receiving diuretics, initiate enalapril 5 mg once daily; if concurrently receiving diuretics and responding to enalaprilat 0.625 mg IV every 6 hours, initiate with enalapril 2.5 mg once daily; subsequent titration as needed.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Use lower listed initial dose in patients with hyponatremia, hypovolemia, severe CHF, decreased renal function, or in those receiving diuretics.

Heart failure: Limited data available: Infants, Children and Adolescents: Oral: Initial: 0.1 mg/kg/day in 1 to 2 divided doses; increase as required over 2 weeks to maximum of 0.5 mg/kg/day; mean dose required for CHF improvement in 39 children (age range: 9 days to 17 years) was 0.36 mg/kg/day; select individuals have been treated with doses up to 0.94 mg/kg/day (Leversha 1994; Momma 2006)

Hypertension: Infants, Children and Adolescents: Oral: Initial: 0.08 mg/kg/dose once daily (maximum dose: 5 mg); adjust dose according to blood pressure readings; doses >0.58 mg/kg (or >40 mg) have not been studied

Proteinuria, nephrotic syndrome: Limited data available: Oral:

Fixed dosing: Children ≥7 years and Adolescents: 2.5 to 5 mg/day was reported in a retrospective study in normotensive pediatric patients as either monotherapy (n=17; mean age: 13.7 years; range: 8 to 17 years) or with prednisone (n=11; mean age: 12.6 years; range: 7 to 16 years); significant decrease in proteinuria (with or without nephrotic syndrome) occurred; no significant change in blood pressure was observed (Sasinka 1999); a case series of three adolescents with sickle anemia nephropathy reported an initial dose of 5 mg/day; one patient required an increase to 7.5 mg/day (Fitzhugh 2005)

Weight-directed dosing: Children and Adolescents: Initial: 0.2 mg/kg/day; titrate to response at 4- to 12-week intervals; range: 0.2 to 0.6 mg/kg/day; maximum daily dose: 20 mg/day; a crossover dose comparison trial showed effects on proteinuria were dose-dependent (Bagga 2004; Chandar 2007; Delucchi 2000; Lama 2000; White 2003); if combined with other angiotensin blockade (ARB), lower doses have been reported (0.1 to 0.16 mg/kg/day) (Chandar 2007)

Reconstitution

Powder for oral solution kit (for 150 mL, enalapril solution 1 mg/mL): Kit contains 1 bottle of enalapril powder and 1 bottle of Ora-Sweet SF dilution to be added to the enalapril powder prior to dispensing. Firmly tap the enalapril powder for oral solution bottle on a hard surface 5 times. Add approximately one-half (75 mL) of the Ora-Sweet SF diluent to the enalapril 150 mL oral solution bottle and shake well for 30 seconds. Add the remainder of the Ora-Sweet SF diluent and shake well for an additional 30 seconds. May be used for 60 days after reconstitution.

Extemporaneously Prepared

Note: Commercial oral solution kit is available (1 mg/mL).

A 1 mg/mL oral suspension may be made with tablets, Bicitra [discontinued] or equivalent, and Ora-Sweet SF. Place ten 20 mg tablets in a 200 mL polyethylene terephthalate bottle; add 50 mL of Bicitra [discontinued] or equivalent and shake well for at least 2 minutes. Let stand for 1 hour then shake for 1 additional minute; add 150 mL of Ora-Sweet SF and shake well. Label "shake well" and "refrigerate". Stable for 30 days when stored in a polyethylene terephthalate bottle and refrigerated (Vasotec prescribing information, 2017).

A 1 mg/mL oral suspension may be made with tablets and one of three different vehicles (cherry syrup, a 1:1 mixture of Ora-Sweet and Ora-Plus, or a 1:1 mixture of Ora-Sweet SF and Ora-Plus). Crush six 20 mg tablets in a mortar and reduce to a fine powder. Add 15 mL of the chosen vehicle and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 120 mL. Label “shake well” and “protect from light”. Stable for 60 days when stored in amber plastic prescription bottles in the dark at room temperature or refrigerated (Allen 1998).

A 1 mg/mL oral suspension may be made with tablets and one of three different vehicles (deionized water, citrate buffer solution at pH 5.0, or a 1:1 mixture of Ora-Sweet and Ora-Plus). Crush twenty 10 mg tablets in a mortar and reduce to a fine powder. Add small portions of the chosen vehicle and mix to a uniform paste; mix while adding vehicle in incremental proportions to almost 200 mL; transfer to a graduated cylinder, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 200 mL. Label "shake well" and "protect from light". Preparations made in citrate buffer solution at pH 5.0 and the 1:1 mixture of Ora-Sweet and Ora-Plus are stable for 91 days when stored in plastic prescription bottles in the dark at room temperature or refrigerated. Preparation made in deionized water is stable for 91 days refrigerated or 56 days at room temperature when stored in plastic prescription bottles in the dark. Note: To prepare the isotonic citrate buffer solution (pH 5.0), see reference (Nahata 1998).

A more dilute, 0.1 mg/mL oral suspension may be made with tablets and an isotonic buffer solution at pH 5.0. Grind one 20 mg tablet in a glass mortar and reduce to a fine powder; mix with isotonic citrate buffer (pH 5.0) and filter; add quantity of buffer solution sufficient to make 200 mL. Label "shake well", "protect from light", and "refrigerate". Stable for 90 days (Boulton 1994).

Allen LV Jr and Erickson MA 3rd. Stability of alprazolam, chloroquine phosphate, cisapride, enalapril maleate, and hydralazine hydrochloride in extemporaneously compounded oral liquids. Am J Health Syst Pharm. 1998;55(18):1915-1920.9784772Boulton DW, Woods DJ, Fawcett JP, et al. The stability of an enalapril maleate oral solution prepared from tablets. Aust J Hosp Pharm. 1994;24(2):151-156.Nahata MC, Morosco RS, and Hipple TF. Stability of enalapril maleate in three extemporaneously prepared oral liquids. Am J Health Syst Pharm. 1998;55(11):1155-1157.9626379Vasotec prescribing information, Valeant Pharmaceuticals North America LLC: Bridgewater, NJ; 2017.

Administration

Oral: Administer without regard to meals.

Dietary Considerations

Limit salt substitutes or potassium-rich diet.

Storage

Oral solution: Store at 2°C to 8°C (36°F to 46°F). Protect from freezing and excessive heat. May store at 20°C to 25°C (68°F to 77°F) for up to 60 days.

Powder for oral solution kit: Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Do not freeze. Protect from moisture. Once reconstituted, the solution should be stored at 15°C to 30°C (59°F to 86°F) and may be stored for up to 60 days.

Tablet: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from moisture.

Drug Interactions

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Aliskiren: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Aliskiren may enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Aliskiren may enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. Management: Aliskiren use with ACEIs or ARBs in patients with diabetes is contraindicated. Combined use in other patients should be avoided, particularly when CrCl is less than 60 mL/min. If combined, monitor potassium, creatinine, and blood pressure closely. Consider therapy modification

Allopurinol: Angiotensin-Converting Enzyme Inhibitors may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Consider therapy modification

Alteplase: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Alteplase. Specifically, the risk for angioedema may be increased. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Angiotensin II: Angiotensin-Converting Enzyme Inhibitors may enhance the therapeutic effect of Angiotensin II. Monitor therapy

Angiotensin II Receptor Blockers: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Angiotensin II Receptor Blockers may increase the serum concentration of Angiotensin-Converting Enzyme Inhibitors. Management: In US labeling, use of telmisartan and ramipril is not recommended. It is not clear if any other combination of an ACE inhibitor and an ARB would be any safer. Consider alternatives to the combination when possible. Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Aprotinin: May diminish the antihypertensive effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

AzaTHIOprine: Angiotensin-Converting Enzyme Inhibitors may enhance the myelosuppressive effect of AzaTHIOprine. Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Bromperidol: Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents. Avoid combination

Dapoxetine: May enhance the orthostatic hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Dexmethylphenidate: May diminish the therapeutic effect of Antihypertensive Agents. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dipeptidyl Peptidase-IV Inhibitors: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk of angioedema may be increased. Monitor therapy

Drospirenone: Angiotensin-Converting Enzyme Inhibitors may enhance the hyperkalemic effect of Drospirenone. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Eplerenone: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Everolimus: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk of angioedema may be increased. Monitor therapy

Ferric Gluconate: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Ferric Gluconate. Monitor therapy

Ferric Hydroxide Polymaltose Complex: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Ferric Hydroxide Polymaltose Complex. Specifically, the risk for angioedema or allergic reactions may be increased. Monitor therapy

Gelatin (Succinylated): Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Gelatin (Succinylated). Specifically, the risk of a paradoxical hypotensive reaction may be increased. Monitor therapy

Gold Sodium Thiomalate: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Gold Sodium Thiomalate. An increased risk of nitritoid reactions has been appreciated. Monitor therapy

Grass Pollen Allergen Extract (5 Grass Extract): Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Grass Pollen Allergen Extract (5 Grass Extract). Specifically, ACE inhibitors may increase the risk of severe allergic reaction to Grass Pollen Allergen Extract (5 Grass Extract). Consider therapy modification

Heparin: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Heparins (Low Molecular Weight): May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Icatibant: May diminish the antihypertensive effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Iron Dextran Complex: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Iron Dextran Complex. Specifically, patients receiving an ACE inhibitor may be at an increased risk for anaphylactic-type reactions. Management: Follow iron dextran recommendations closely regarding both having resuscitation equipment and trained personnel on-hand prior to iron dextran administration and the use of a test dose prior to the first therapeutic dose. Consider therapy modification

Lanthanum: May decrease the serum concentration of Angiotensin-Converting Enzyme Inhibitors. Management: Administer angiotensin-converting enzyme inhibitors at least two hours before or after lanthanum. Consider therapy modification

Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Monitor therapy

Lithium: Angiotensin-Converting Enzyme Inhibitors may increase the serum concentration of Lithium. Management: Lithium dosage reductions will likely be needed following the addition of an ACE inhibitor. Monitor patient response to lithium closely following addition or discontinuation of concurrent ACE inhibitor treatment. Consider therapy modification

Loop Diuretics: May enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Loop Diuretics may enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Potassium Salts: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Potassium-Sparing Diuretics: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Pregabalin: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Pregabalin. Specifically, the risk of angioedema may be increased. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Racecadotril: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk for angioedema may be increased with this combination. Monitor therapy

Ranolazine: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Sacubitril: Angiotensin-Converting Enzyme Inhibitors may enhance the adverse/toxic effect of Sacubitril. Specifically, the risk of angioedema may be increased with this combination. Avoid combination

Salicylates: May enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. Salicylates may diminish the therapeutic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Sirolimus: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Sodium Phosphates: Angiotensin-Converting Enzyme Inhibitors may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with ACEIs, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, maintain adequate hydration and monitor renal function closely. Consider therapy modification

Tacrolimus (Systemic): Angiotensin-Converting Enzyme Inhibitors may enhance the hyperkalemic effect of Tacrolimus (Systemic). Monitor therapy

Temsirolimus: May enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Thiazide and Thiazide-Like Diuretics: May enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Thiazide and Thiazide-Like Diuretics may enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

TiZANidine: May enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Tolvaptan: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Trimethoprim: May enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Urapidil: May interact via an unknown mechanism with Angiotensin-Converting Enzyme Inhibitors. Management: Avoid concomitant use of urapidil and angiotensin-converting enzyme (ACE) inhibitors. Consider therapy modification

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Test Interactions

May lead to false-negative aldosterone/renin ratio (Funder 2016)

Adverse Reactions

Note: Frequency ranges include data from hypertension and heart failure trials. Higher rates of adverse reactions have generally been noted in patients with CHF. However, the frequency of adverse effects associated with placebo is also increased in this population.

>10%: Renal: Increased serum creatinine (≤20%)

1% to 10%:

Cardiovascular: Hypotension (1% to 7%), chest pain (2%), orthostatic effect (1% to 2%), orthostatic hypotension (2%), syncope (≤2%)

Central nervous system: Dizziness (4% to 8%), headache (2% to 5%), fatigue (2% to 3%)

Dermatologic: Skin rash (1% to 2%)

Gastrointestinal: Abdominal pain, anorexia, constipation, diarrhea, dysgeusia, nausea, vomiting

Neuromuscular & skeletal: Weakness

Renal: Renal insufficiency (in patients with bilateral renal artery stenosis or hypovolemia)

Respiratory: Bronchitis (1% to 2%), cough (1% to 2%), dyspnea (1% to 2%)

<1%, postmarketing, and/or case reports: Abnormal dreams, acute generalized exanthematous pustulosis, agranulocytosis, alopecia, anaphylactoid reaction, angina pectoris, angioedema, anosmia, arthralgia, arthritis, asthma, ataxia, atrial fibrillation, atrial tachycardia, blurred vision, bone marrow depression, bradycardia, bronchospasm, cardiac arrest, cardiac arrhythmia, cerebrovascular accident, cholestatic jaundice, confusion, conjunctivitis, depression, diaphoresis, drowsiness, dry eye syndrome, dyspepsia, eosinophilia, eosinophilic pneumonitis, erythema multiforme, exfoliative dermatitis, fever, flank pain, flushing, giant-cell arteritis, glossitis, gynecomastia, hallucination, hemolysis (with G6PD), hepatitis, herpes zoster, hoarseness, IgA vasculitis, increased erythrocyte sedimentation rate, intestinal obstruction, impotence, insomnia, interstitial nephritis, jaundice, lacrimation, leukocytosis, lichenoid eruption, melena, muscle cramps, myocardial infarction, myalgia, myositis, nervousness, neutropenia, ototoxicity, palpitations, pancreatitis, paresthesia, pemphigus, pemphigus foliaceus, peripheral neuropathy, positive ANA titer, pruritus, psychosis, pulmonary edema, pulmonary embolism, pulmonary infarct, pulmonary infiltrates, Raynaud's phenomenon, rhinorrhea, serositis, Sjogren's syndrome, skin photosensitivity, sore throat, Stevens-Johnson syndrome, stomatitis, systemic lupus erythematosus, thrombocytopenia, tinnitus, toxic epidermal necrolysis, upper respiratory tract infection, urticaria, vasculitis, vertigo, visual hallucination (Doane, 2013), xerostomia

Warnings/Precautions

Concerns related to adverse effects:

• Angioedema: At any time during treatment (especially following first dose) angioedema may occur rarely with angiotensin-converting enzyme (ACE) inhibitors; it may involve the head and neck (potentially compromising airway) or the intestine (presenting with abdominal pain). African-Americans may be at an increased risk. Risk may also be increased with concomitant use of mTOR inhibitor (eg, everolimus) therapy or a neprilysin inhibitor (eg, sacubitril). Prolonged frequent monitoring may be required especially if tongue, glottis, or larynx are involved as they are associated with airway obstruction. Patients with a history of airway surgery may have a higher risk of airway obstruction. Aggressive early and appropriate management is critical. Use in patients with idiopathic or hereditary angioedema or previous angioedema associated with ACE inhibitor therapy is contraindicated.
• Cholestatic jaundice: A rare toxicity associated with ACE inhibitors includes cholestatic jaundice, which may progress to fulminant hepatic necrosis (some fatal); discontinue if marked elevation of hepatic transaminases or jaundice occurs.
• Cough: An ACE inhibitor cough is a dry, hacking, nonproductive one that usually occurs within the first few months of treatment and should generally resolve within 1 to 4 weeks after discontinuation of the ACE inhibitor. Other causes of cough should be considered (eg, pulmonary congestion in patients with heart failure) and excluded prior to discontinuation.
• Hematologic effects: Another ACE inhibitor, captopril, has been associated with neutropenia with myeloid hypoplasia and agranulocytosis; anemia and thrombocytopenia have also occurred. Patients with renal impairment are at high risk of developing neutropenia. Patients with both renal impairment and collagen vascular disease (eg, systemic lupus erythematosus) are at an even higher risk of developing neutropenia. Periodically monitor CBC with differential in these patients.
• Hyperkalemia: May occur with ACE inhibitors; risk factors include renal dysfunction, diabetes mellitus, concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salts. Use cautiously, if at all, with these agents and monitor potassium closely.
• Hypersensitivity reactions: Anaphylactic/anaphylactoid reactions can occur with ACE inhibitors. Severe anaphylactoid reactions may be seen during hemodialysis (eg, CVVHD) with high-flux dialysis membranes (eg, AN69), and rarely, during low density lipoprotein apheresis with dextran sulfate cellulose. Rare cases of anaphylactoid reactions have been reported in patients undergoing sensitization treatment with hymenoptera (bee, wasp) venom while receiving ACE inhibitors.
• Hypotension/Syncope: Symptomatic hypotension with or without syncope can occur with ACE inhibitors (usually with the first several doses). Effects are most often observed in volume-depleted patients; correct volume depletion prior to initiation. Close monitoring of patient is required, especially with initial dosing and dosing increases; blood pressure must be lowered at a rate appropriate for the patient's clinical condition. Although dose reduction may be necessary, hypotension is not a reason for discontinuation of future ACE inhibitor use, especially in patients with HF where a reduction in systolic blood pressure is a desirable observation.
• Renal function deterioration: May be associated with deterioration of renal function and/or increases in serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, heart failure) whose GFR is dependent on efferent arteriolar vasoconstriction by angiotensin II; deterioration may result in oliguria, acute renal failure, and progressive azotemia. Small increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function (Bakris 2000).

Disease-related concerns:

• Aortic stenosis: Use with caution in patients with severe aortic stenosis; may reduce coronary perfusion resulting in ischemia.
• Ascites: Avoid use in patients with ascites due to cirrhosis or refractory ascites; if use cannot be avoided in patients with ascites due to cirrhosis, monitor blood pressure and renal function carefully to avoid rapid development of renal failure (AASLD [Runyon 2012]).
• Cardiovascular disease: Initiation of therapy in patients with ischemic heart disease or cerebrovascular disease warrants close observation due to the potential consequences posed by falling blood pressure (eg, MI, stroke). Fluid replacement, if needed, may restore blood pressure; therapy may then be resumed. Discontinue therapy in patients whose hypotension recurs.
• Collagen vascular disease: Use with caution in patients with collagen vascular disease especially with concomitant renal impairment; may be at increased risk for hematologic toxicity.
• Hypertrophic cardiomyopathy with outflow tract obstruction: Use with caution in patients with hypertrophic cardiomyopathy and outflow tract obstruction since reduction in afterload may worsen symptoms associated with this condition (ACC/AHA [Gersh 2011]).
• Renal artery stenosis: Use with caution in patients with unstented unilateral/bilateral renal artery stenosis. When unstented bilateral renal artery stenosis is present, use is generally avoided due to the elevated risk of deterioration in renal function unless possible benefits outweigh risks.
• Renal impairment: Use with caution in preexisting renal insufficiency; dosage adjustment may be needed. Avoid rapid dosage escalation which may lead to further renal impairment. In a retrospective cohort study of elderly patients (≥65 years of age) with myocardial infarction and impaired left ventricular function, administration of an ACE inhibitor was associated with a survival benefit, including patients with serum creatinine concentrations >3 mg/dL (265 micromol/L) (Frances 2000).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Black patients: ACE inhibitors effectiveness is less in black patients than in non-blacks. In addition, ACE inhibitors cause a higher rate of angioedema in black than in non-black patients.
• Pregnancy: [US Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected.
• Surgical patients: In patients on chronic ACE inhibitor therapy, intraoperative hypotension may occur with induction and maintenance of general anesthesia; use with caution before, during, or immediately after major surgery. Cardiopulmonary bypass, intraoperative blood loss, or vasodilating anesthesia increases endogenous renin release. Use of ACE inhibitors perioperatively will blunt angiotensin II formation and may result in hypotension. However, discontinuation of therapy prior to surgery is controversial. If continued preoperatively, avoidance of hypotensive agents during surgery is prudent (Hillis 2011). Based on current research and clinical guidelines in patients undergoing non-cardiac surgery, continuing ACE inhibitors is reasonable in the perioperative period. If ACE inhibitors are held before surgery, it is reasonable to restart postoperatively as soon as clinically feasible (ACC/AHA [Fleisher 2014]).

Dosage forms specific issues:

• Benzyl alcohol and derivatives: Oral solution: May contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol. Large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP 1997; CDC 1982). Some data suggest that benzoate displaces bilirubin from protein-binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.

Monitoring Parameters

Blood pressure; serum creatinine and potassium; if patient has collagen vascular disease and/or renal impairment, periodically monitor CBC with differential

Heart Failure: Within 1 to 2 weeks after initiation and periodically thereafter, reassess renal function and serum potassium especially in patients with preexisting hypotension, hyponatremia, diabetes mellitus, azotemia, or those taking potassium supplements (ACC/AHA [Yancy 2013; Yancy 2017]).

Hypertension: The 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults (ACC/AHA [Whelton 2018]):

Confirmed hypertension and known cardiovascular disease or 10-year atherosclerotic cardiovascular disease risk ≥10%: Target blood pressure <130/80 mm Hg is recommended

Confirmed hypertension without markers of increased atherosclerotic cardiovascular disease risk: Target blood pressure <130/80 mm Hg may be reasonable

Diabetes and hypertension: The American Diabetes Association (ADA) guidelines (ADA 2019):

Patients 18 to 65 years of age, without atherosclerotic cardiovascular disease (ASCVD), and 10-year ASCVD risk <15%: Target blood pressure <140/90 mm Hg is recommended.

Patients 18 to 65 years of age and known ASCVD or 10-year ASCVD risk >15%: Target blood pressure <130/80 mm Hg may be appropriate if it can be safely attained.

Patients >65 years of age (healthy or complex/intermediate health): Target blood pressure <140/90 mm Hg is recommended.

Patients >65 years of age (very complex/poor health): Target blood pressure <150/90 mm Hg is recommended.

Pregnancy

Pregnancy Considerations

Enalapril crosses the placenta; the active metabolite enalaprilat can be detected in the newborn (Schubiger 1988).

Exposure to an angiotensin-converting enzyme (ACE) inhibitor during the first trimester of pregnancy may be associated with an increased risk of fetal malformations (ACOG 203 2019; ESC [Regitz-Zagrosek 2018]); however, outcomes observed may also be influenced by maternal disease (ACC/AHA [Whelton 2017]).

[US Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected.

Drugs that act on the renin-angiotensin system are associated with oligohydramnios. Oligohydramnios, due to decreased fetal renal function, may lead to fetal lung hypoplasia and skeletal malformations. The use of these drugs in pregnancy is also associated with anuria, hypotension, renal failure, skull hypoplasia, and death in the fetus/neonate. Infants exposed to an ACE inhibitor in utero should be monitored for hyperkalemia, hypotension, and oliguria. Oligohydramnios may not appear until after irreversible fetal injury has occurred. Exchange transfusions or dialysis may be required to reverse hypotension or improve renal function, although data related to the effectiveness in neonates is limited.

Chronic maternal hypertension is also associated with adverse events in the fetus/infant. Chronic maternal hypertension may increase the risk of birth defects, low birth weight, premature delivery, stillbirth, and neonatal death. Actual fetal/neonatal risks may be related to duration and severity of maternal hypertension. Untreated chronic hypertension may also increase the risks of adverse maternal outcomes, including gestational diabetes, preeclampsia, delivery complications, stroke, and myocardial infarction (ACOG 203 2019).

When treatment of hypertension in pregnancy is indicated, ACE inhibitors should generally be avoided due to their adverse fetal events; use in pregnant women should only be considered for cases of hypertension refractory to other medications (ACOG 203 2019). ACE inhibitors are not recommended for the treatment of heart failure in pregnancy (Regitz-Zagrosek [ESC 2018]).

ACE inhibitors should be avoided in sexually active females of reproductive potential not using effective contraception (ADA 2020). ACE inhibitors should generally be avoided for the treatment of hypertension in women planning a pregnancy; use should only be considered for cases of hypertension refractory to other medications (ACOG 203 2019). When treatment is needed in females of reproductive potential with diabetic nephropathy, the ACE inhibitor should be discontinued at the first positive pregnancy test (Cabiddu 2016; Spotti 2018).

Patient Education

What is this drug used for?

• It is used to treat high blood pressure.
• It is used to treat heart failure (weak heart).
• It is used in certain patients with heart failure to lower the chance of having to go to the hospital for heart failure that gets worse.
• It may be given to you for other reasons. Talk with the doctor.

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.
• High potassium like abnormal heartbeat, confusion, dizziness, passing out, weakness, shortness of breath, or numbness or tingling feeling.
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Severe dizziness
• Passing out
• Persistent cough
• Chest pain
• Severe abdominal pain
• Severe nausea
• Vomiting
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.